Background: The effects of weather on West Nile virus (WNV) mosquito populations in the United States have been widely reported, but few studies assess their overall impact on transmission to humans. Objectives: We investigated meteorologic conditions associated with reported human WNV cases in the United States. Methods: We conducted a case–crossover study to assess 16,298 human WNV cases reported to the Centers for Disease Control and Prevention from 2001 to 2005. The primary outcome measures were the incidence rate ratio of disease occurrence associated with mean weekly maximum temperature, cumulative weekly temperature, mean weekly dew point temperature, cumulative weekly precipitation, and the presence of ≥ 1 day of heavy rainfall (≥ 50 mm) during the month prior to symptom onset. Results: Increasing weekly maximum temperature and weekly cumulative temperature were similarly and significantly associated with a 35–83% higher incidence of reported WNV infection over the next month. An increase in mean weekly dew point temperature was significantly associated with a 9–38% higher incidence over the subsequent 3 weeks. The presence of at least 1 day of heavy rainfall within a week was associated with a 29–66% higher incidence during the same week and over the subsequent 2 weeks. A 20-mm increase in cumulative weekly precipitation was significantly associated with a 4–8% increase in incidence of reported WNV infection over the subsequent 2 weeks. Conclusions: Warmer temperatures, elevated humidity, and heavy precipitation increased the rate of human WNV infection in the United States independent of season and each others’ effects.